PROJECT 4: Even though cigarette smoke (CS) exposure is the most recognized risk factor for COPD, genetic, environmental and developmental factors certainly contribute to the pathophysiology of this debilitating disease. Substantial epidemiological data indicate that impaired alveolar growth during infant life may increase the risk of developing CS-induced COPD in adults. Individuals exposed to high levels of pollutants in early life are at increased risk for sub-optimal lung growth as adults and parental smoking in childhood is associated with poorer lung function in adulthood. Our long term objective is to understand the mechanisms that cause increased susceptibility of developing lungs to pollutants that manifests itself as impaired lung function in adult life. Our preliminary studies have shown that the Nrf2 transcription factor plays a central role in counteracting the oxidative insult of CS. Developing mice have marked decrease in pulmonary Nrf2 activity as well as greater inflammation even after shorter CS exposure, relative to adult mice. Decreased Nrf2 activity is associatedwith increased TGF beta activation, greater oxidative stress and alveolar cell apoptosis in response to CS in developing lungs. We hypothesize that developing lung are intrinsically susceptible to oxidative insult by environmental pollutants such as CS, due to the lower Nrf2 activity. These injuries in the developing lungs lead to an abnormal lung structure in adult life, with enhanced predisposition to the development of emphysema upon re-exposure to CS or pollutants. We will test this hypothesis using the Nrf2 +/+,-/- and Nrf2 over-expressing transgenic mice. Finally, we will determine the association of genetic variation in Nrf2 gene and its activity with development of COPD in humans. We will find polymorphisms of the NRF2 gene and determine if it is associated with susceptibility and progression of COPD. This project will interact closely with Project 1 on a joint aim regarding a-1 antitrypsin efficiency, and will receive human biological specimens from Projects 2 and 5. This project will make use of Core D for histology, and physiologic measurements and Core C for ADC measurements of terminal airspace dimension.